The sites and mechanisms of cocaine induced cardiorespiratory failure are unknown. Both cocaine and pro-cocaine produce apneusis at the caudal ventrolateral medulla (CVLM). Pre-treatment of the CVLM with the anti- cholinesterase physostigmine (PHYS) inhibits cocaine-induced apneusis (CIA). The aims of this application are to evaluate the effects of PHYS pre-treatment on pro-cocaine induced apneusis. To elucidate the mechanism of action of PHYS and to study excitatory amino acid (EAA) implications in CIA. Acetylcholinesterase hydrolysis of neuropeptides and apneusis after EAA blockade suggest involvement of substance P, opiates and EAA in CIA. Studies will be performed on the cholinomimetic property of PHYS by pre- treatment of the CVLM with PHYS + atropine and/or PHYS + hexamethonium prior to cocaine. Substance P, opiates, and agonists/antagonists of EAA receptors will also be evaluated for their ability to inhibit CIA. Experiments will be carried out in urethane anesthetized (2.0g/kg) cats. Drugs will be applied topically to the CVLM using small filter paper pledgets (5-ul). Tidal volume (VT), respiratory frequency (f), minute ventilation (VE), heart rate, systolic, diastolic and mean arterial pressures will be monitored. Statistical significance of differences, with and without pre-treatments, will be determined by ANOVA. Results will provide new knowledge about PHYS counter-action of CIA and EAA mechanisms in cocaine-induced cardiorespiratory failure.